The focus of this application is on the molecular mechanisms of action of genetically controlled elements in autoimmunity. the overall objective of this program is to identify, study, and understand several of the key genetic parameters which underlie disease susceptibility and autoimmune activation. Project 1 investigates the molecular interactions which trigger cellular activation in immune-mediated events in autoimmunity. The specific objective is to identify and dissect the critical structural characteristics of T cell receptor molecules which can interact with HLA-DR elements implicated by prior genetic analyses as being involved in susceptibility to autoimmune disease. Project 2 evaluates the role of intra-cellular molecular interactions in autoimmunity, specifically, class II-peptide interactions and affinities during antigen presentation. Project 3 focuses one step back on the pathway of HLA contributions to autoimmunity, evaluating the role of promoter region polymorphisms relative to transcriptional activity associated with HLA-DR susceptibility genes. Project 4 will evaluate the VH repertoire and its relationship to germline encoded autoantibodies. Each of these projects is likely to define critical elements of the immune response pathway and lead to a better understanding of the molecular and genetic mechanisms of autoimmunity. This is a highly technical, detail-oriented proposal, emphasizing new ideas and new initiatives. We have specifically selected innovative, non- traditional approaches to important questions in autoimmunity, as we feel that this orientation is timely, building upon work by us and others over the past decade which has focused on identifying candidate susceptibility genes for autoimmunity. The innovative nature of these projects and their common emphasis on molecular mechanisms invite high degree of technical and conceptual synergy well suited for a program project.